PPAR gamma agonist, pioglitazone, rescues liver damage induced by renal ischemia/reperfusion injury

Remote organ damage is the major cause of death in patients with acute kidney injury (AKI) due to renal ischemia reperfusion (IR). Liver is one of the vital organs which are profoundly affected by AKI. The present study aims to investigate the role of peroxisome proliferator activator receptor gamma (PPAR gamma) in liver damage induced by IR injury in rats. Renal IR was induced by right nephrectomy, occlusion of left renal pedicle for 45 min to induce ischemia, and then reperfusion for 6 or 24 h. The PPAR gamma agonist, pioglitazone, was given orally for 7 days before renal IR procedure. Animals receiving pioglitazone showed improvement in renal and hepatic functions when compared to IR groups. Renal IR increased renal, hepatic and serum levels of tumor necrosis factor-alpha (TNF-alpha) and induced apoptotic cell death in liver. These effects were diminished with pioglitazone. In addition, pioglitazone reduced renal IR-induced oxidative stress in liver. Pioglitazone reduced malondialdehyde (MDA) content and NADPH oxidase mRNA expression and induced further increase in nuclear factor erythroid 2-related factor 2 (Nrf2) expression when compared to IR groups. Furthermore, pioglitazone increased the expression of PPAR gamma target genes such as renal and hepatic PPAR gamma 1 (Pparg1), hepatic hemoxygenase-1 (Hmox1), and hepatic thioredoxin (TRx). Histological profiles for kidney and liver were also ameliorated with pioglitazone. Hence, PPAR gamma is a potential target to protect liver in patients with renal IR injury.